Journal
CARDIOVASCULAR RESEARCH
Volume 97, Issue 1, Pages 115-124Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvs284
Keywords
Angiogenesis; Gene therapy; HO-1; MicroRNA; Satellite cells
Categories
Funding
- Foundation for Polish Science [Homing-Plus/2011-3/3]
- Ministry of Science and Higher Education/National Science Centre [N301 314837]
- Ministry of Science and Higher Education
- Foundation for Polish Science
- Wellcome Trust
- European Union [POIG.02.01.00-12-064/08, POIG.02.02.00-014/08, POIG.01.01.02-00-069/09]
- COST Action [TD0901 HypoxiaNet]
- [POIG 01.01.02-00-109/99]
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Haem oxygenase-1 (HO-1) is a haem-degrading enzyme that generates carbon monoxide, bilirubin, and iron ions. Through these compounds, HO-1 mitigates cellular injury by exerting antioxidant, anti-apoptotic, and anti-inflammatory effects. Here, we examined the influence of HO-1 deficiency and transient hypoxia/ischaemia-induced HO-1 overexpression on post-injury hindlimb recovery. Mice lacking functional HO-1 (HO-1(/)) showed reduced reparative neovascularization in ischaemic skeletal muscles, impaired blood flow (BF) recovery, and increased muscle cell death compared with their wild-type littermates. Human microvascular endothelial cells (HMEC-1) transfected with plasmid vector (pHRE-HO-1) carrying human HO-1 driven by three hypoxia response elements (HREs) and cultured in 0.5 oxygen demonstrated markedly increased expression of HO-1. Such upregulated HO-1 levels were effective in conferring protection against H2O2-induced cell death and in promoting the proangiogenic phenotype of HMEC-1 cells. More importantly, when delivered in vivo, pHRE-HO-1 significantly improved the post-ischaemic foot BF in mice subjected to femoral artery ligation. These effects were associated with reduced levels of pro-inflammatory cytokines (IL-6 and CXCL1) and lower numbers of transferase-mediated dUTP nick-end labelling-positive cells. Moreover, HO-1 delivered into mouse skeletal muscles seems to influence the regenerative potential of myocytes as it significantly changed the expression of transcriptional (Pax7, MyoD, myogenin) and post-transcriptional (miR-146a, miR-206) regulators of skeletal muscle regeneration. Our results suggest the therapeutic potential of HO-1 for prevention of adverse effects in critical limb ischaemia.
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